Expression of the pituitary-specific transcription factor, pit- 1, in the anterior pituitary is crucial for the development of the somatotroph, lactotroph and thyrotroph lineages and expression of their hormone products. During pituitary development, activation of the pit-1 gene is accomplished by autoregulation of a distal enhancer element by pit-1 and retinoic acid. After pituitary development is completed, pit-1 is also necessary for expression and regulation of growth hormone (GH), prolactin (Prl), and thyrotropin (TSH) through a number of elements present on these target genes. In particular, the activation of the GH gene by growth hormone releasing hormone is under regulation by the protein kinase A (PKA)-dependent signaling pathway. This proposal will test whether a recently described coactivator, CREB binding protein (CBP), functions to regulate pit-1-dependent GH gene expression in the anterior pituitary. The role of CBP in PKA signaling will be established, and the critical domains on CBP and pit-1 for these responses will be characterized. The role of CBP in other signaling pathways will also be explored. Unique insight into these signaling pathways will be gained from the study of Pit-1 gene mutations from patients with combined pituitary hormone deficiency of GH, Prl, and TSH. Determination of CBP's role as a cofactor for pit-1 action will further our understanding of cell-specific GH gene regulation in health and disease.